YNHH Laboratory Manual

Warfarin Warfarin (Coumadin®, Bristol-Myers Squibb) is monitored by the international normalized ratio (INR), which is calculated from the prothrombin time (PT). The INR was developed to account for the variability among PT reagents (thromboplastins) used by different laboratories, which gives rise to varying PT results for the same intensity of anticoagulation. The INR, therefore allows for standardization of warfarin monitoring between laboratories. The INR is calculated from the following formula:

INR = (patient PT/mean normal PT)^ISI

where ISI is the sensitivity measure of the particular thromboplastin used by the lab performing the PT. The INR is reported out automatically with the PT.

The target INR for most anticoagulation indications is 2.0 - 3.0. For some patients at very high thrombotic risk, the target INR is 2.5 - 3.5.

See the following references for complete guidelines on target INR ranges and warfarin monitoring:

Ansell [et al]., The pharmacology and management of the vitamin K antagonists. The seventh ACCP conference on antithrombotic and thrombolytic therapy. [Chest] 2004;126:204S-233S.

Buller [et al]., Antithrombotic therapy for venous thromboembolic disease: The seventh ACCP conference on antithrombotic and thrombolytic therapy. [Chest] 2004;126:401S-428S.

Deeb [et al]., Antithrombotic therapy in valvular heart disease - native and prosthetic. The seventh ACCP conference on antithrombotic and thrombolytic therapy. [Chest] 2004;126:457S-482S.

[[http://www.coumadin.com]] (includes link to warfarin package insert)

Heparins

Unfractionated heparin

Therapeutic unfractionated heparin anticoagulation intensity is monitored by the aPTT, which is used as a surrogate measurement for the anti-Xa activity. The therapeutic range for heparin is an anti-Xa activity level between 0.3 and 0.7 units/ml. This corresponds to an aPTT of approximately 56 - 96 seconds at YNHH. The aPTT should be measured every six hours during the first 24 hours of heparin therapy, six hours after any dose change and at least once daily while receiving a stable intravenous dose by continuous infusion. Occasional patients will not exhibit satisfactory aPTT prolongations despite escalating doses of heparin. This heparin resistance is often present in patients with systemic inflammation who have high levels of circulating acute phase reactants. Acute phase proteins bind heparin and neutralize its anticoagulant activity. In addition, factor VIII is often increased as an acute phase reactant and may falsely decrease the aPTT. An anti-Xa level may be helpful if heparin resistance is suspected. Heparin resistance does not occur with low molecular weight heparins, because plasma protein binding to these smaller molecules is minimal.

Rarely, therapeutic unfractionated heparin is administered twice daily via the subcutaneous route. Heparin absorption is variable in this situation, but dose adjustments based on aPTT measurements six hours after dosing have been used successfully in clinical trials.

Subcutaneous prophylactic heparin is generally administered without laboratory monitoring. In the event of bleeding complications in patients receiving prophylactic doses, however, the aPTT can be used to assess the intensity of anticoagulation.

Low molecular weight heparins (LMWH)

Low molecular weight heparins (enoxaparin (Lovenox®, Sanofi-Aventis), dalteparin (Fragmin®, Pfizer), tinzaparin (Innohep®, Pharmion), fondaparinux (Arixtra®, GlaxoSmithKline) are administered without laboratory monitoring. Their near 100% bioavailability via the subcutaneous route and low plasma protein binding allow for consistent anticoagulation with fixed, weight-based dosing without monitoring in most patient populations. Low molecular weight heparins prolong the aPTT only minimally because of their low anti-IIa activity relative to anti-Xa activity; therefore, in the rare circumstance in which laboratory monitoring is advisable, the aPTT cannot serve as a surrogate for anti-Xa activity, and anti-Xa activity must be measured directly. Most clinical trials in which low molecular weight heparins were used to treat acute venous thromboembolism did not use target anti-Xa levels to guide dosing, hence therapeutic levels have been determined retrospectively. The table summarizes guidelines for therapeutic low molecular weight heparin levels for the various formulations available in the US. Anti-Xa levels should be determined in a plasma sample that has been drawn approximately [4 hours after] a dose of LMWH.

There is no clear-cut association between clinical efficacy and peak anti-Xa levels in the treatment of acute venous thromboembolism; however, bleeding complications appear to be increased in patients with renal impairment at anti-Xa activity levels >1.0 u/ml due to accumulation of drug which is normally renally excreted. The use of anti-Xa activity levels for monitoring LMWH should therefore be limited to patients at risk for bleeding due to overdosing when standard weight-based doses are administered, such as those with severe renal insufficiency or obesity (weight > 150 kg). In these cases, anti-Xa levels in steady-state should be used to guide dose-reduction to avoid exceeding recommended peak levels. The use of unfractionated heparin with aPTT monitoring is recommended for patients with severe renal insufficiency. LMWH may be administered without monitoring, with no compromise in efficacy or safety, to patients weighing up to 150 kg.

Monitoring prophylactic dose LMWH is not routinely performed, thus guidelines for target peak anti-Xa levels are not available. Levels between 0.2 and 0.5 u/ml may be appropriate.

References

Buller [et al]., Antithrombotic therapy for venous thromboembolic disease: The seventh ACCP conference on antithrombotic and thrombolytic therapy. [Chest] 2004;126:401S-28S.

Davidson [et al]., Effect of obesity of outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials. [J Thromb Haemost] 2007;5:1191-94.

Hirsch and Raschke. Heparin and low molecular weight heparin: The seventh ACCP conference on antithrombotic and thrombolytic therapy. [Chest] 2004;126:188S-203S.

Lim [et al]., Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. [Ann Intern Med] 2006;144:673-84.

Prandoni [et al]., Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. [Arch Intern Med] 2004;164:1077-83.

[[http://www.fragmin.com]] (includes link to dalteparin package insert)

[[http://www.lovenox.com]] (includes link to enoxaparin package insert)

[[http://www.arixtra.com]] (includes link to fondaparinux package insert)

[[http://www.innohepusa.com]] (includes link to tinzaparin package insert)

Direct Thrombin Inhibitors

The direct thrombin inhibitors, lepirudin and argatroban, are used for prevention and treatment of thrombosis in patients with heparin induced thrombocytopenia. These drugs specifically inhibit thrombin activity and therefore prolong both the PT and aPTT. The aPTT is currently used to monitor the anticoagulant intensity of both of these drugs, and the risk of major bleeding is proportional to the degree of aPTT prolongation. When overlapping with warfarin treatment, the PT and INR may overestimate the warfarin anticoagulation effect because of the effect of the thrombin inhibitors on the PT. This must be taken into account when transitioning from a direct thrombin inhibitor to warfarin.

Lepirudin

Lepirudin (Refludan®, Bayer) is recombinant hirudin, a polypeptide thrombin inhibitor that is administered intravenously by bolus followed by continuous infusion, and has a plasma half-life of approximately 80 minutes. The target aPTT with lepirudin is 1.5 to 2.5X the midpoint of the normal aPTT range. The aPTT should be measured at baseline before starting the lepirudin infusion, 4 hours after initiation and 4 hours after any dose change. For patients on a stable dose, the aPTT should be measured at least once daily. Lepirudin is renally excreted; therefore, monitoring in patients with renal insufficiency or other risk factors for bleeding [e.g] severe liver disease) should be done more frequently. Lepirudin should not be started if the baseline aPTT is >2.5X the midpoint of the normal range.

Lepirudin has only a modest effect on the PT, thus transition to warfarin may be monitored with the INR. The INR may be decreased somewhat upon discontinuation of lepirudin, however, so this should be considered when adjusting warfarin dose during the transition.

Argatroban

Argatroban (!GlaxoSmithKline) is a synthetic small molecule thrombin inhibitor that is administered intravenously by bolus followed by continuous infusion, and has a plasma half-life of approximately 45 minutes. The target aPTT with argatroban is 1.5 to 3X the midpoint of the normal aPTT range, not exceeding 100 seconds. The aPTT should be measured at baseline before starting the argatroban infusion, 2 hours after initiation and 2 hours after any dose change. For patients on a stable dose, the aPTT should be measured at least once daily. Argatroban is metabolized by the liver; therefore, monitoring in patients with hepatic insufficiency or other risk factors for bleeding should be done more frequently than once daily. Argatroban should not be started if the baseline aPTT is >3X the midpoint of the normal range.

When argatroban is used during percutaneous coronary interventions (PCI) the anticoagulant effect is monitored with the activated clotting time (ACT). The target ACT range is 300 - 450 seconds, and should be measured 5 - 10 minutes after argatroban bolus or infusion dose change and every 20 to 30 minutes in patients on a stable dose during a prolonged procedure.

Argatroban increases the INR more than lepirudin. The following formula may be used to estimate the warfarin contribution to increased INR (INR_W) when both drugs are administered concurrently:

INR_W = 0.18 + 0.45(INR_WA)

Where INR_WA = Measured INR for a patient receiving concurrent argatroban and warfarin. This formula is associated with an error of +/- 0.4 INR unit and is NOT valid for argatroban doses above 2 µg/kg/min. The INR due to warfarin alone may be determined on a sample drawn 4 - 6 hours after discontinuation of argatroban.

Bivalirudin

Bivalirudin (Angiomax®, BenVenue Laboratories) is a synthetic peptide thrombin inhibitor that is administered intravenously by bolus followed by continuous infusion, and has a plasma half-life of approximately 25 minutes. Bivalifudin is approved for use only during percutaneous coronary interventions (PCI). The anticoagulant effect is monitored once with the ACT, which is measured 5 minutes after the initial bolus dose. If the ACT is less than 350 seconds a second bolus dose is administered. The ACT is not generally monitored subsequently.

For complete dosing and monitoring guidelines for the direct thrombin inhibitors see:

http://www.refludan.com (includes link to lepirudin package insert)

http://www.argatroban.com (includes link to argatroban package insert)

http://www.angiomax.com (includes link to bivalirudin package insert)

Warkentin and Greinacher. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: The seventh ACCP conference on antithrombotic and thrombolytic therapy. [Chest] 2004;126:S311-S37.

Updated: July-2008